Abstract
Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non-small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that ALK resistance mutations may represent a biomarker of response in previously treated patients. Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non-small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK mutation-focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to ALK mutation status. Approximately one quarter of patients had ALK mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, the efficacy of lorlatinib was comparable among patients with and without ALK mutations using plasma or tissue genotyping. In contrast, in patients who had failed 1 or more second-generation ALK TKIs, objective response rate was higher among patients with ALK mutations (62% v 32% [plasma]; 69% v 27% [tissue]). Progression-free survival was similar in patients with and without ALK mutations on the basis of plasma genotyping (median, 7.3 months v 5.5 months; hazard ratio, 0.81) but significantly longer in patients with ALK mutations identified by tissue genotyping (median, 11.0 months v 5.4 months; hazard ratio, 0.47). In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib.
Highlights
Clinical characteristics of the larger group of EXP3B to EXP5 patients according to anaplastic lymphoma kinase (ALK) mutation status are shown in the Data Supplement
Median progression-free survival (PFS) was 11.0 months versus 4.0 months in patients with and without ALK mutations, respectively (HR, 0.20; 95% CI, 0.10 to 0.40; Data Supplement). These findings suggest that in patients who have previously received one or more second-generation ALK inhibitors, the presence of an ALK mutation based on tissue genotyping may identify a subgroup of patients more likely to derive durable benefit from lorlatinib
We examined the efficacy of lorlatinib according to the exact ALK mutation identified by plasma or tissue genotyping
Summary
A total of 228 patients with ALK-positive NSCLC were enrolled in the phase II study. Thirty ALK-positive patients who were treatment naıve (expansion cohort 1 [EXP1]) were excluded from this analysis. Median DOR was 24.4 months in mutation-positive patients compared with 4.3 months in mutation-negative patients (Data Supplement) These differences were more pronounced when tumor tissue genotyping was limited to de novo biopsies. Median PFS was 11.0 months (95% CI, 6.9 months to 25.6 months) versus 4.0 months (95% CI, 2.6 months to 5.5 months) in patients with and without ALK mutations, respectively (HR, 0.20; 95% CI, 0.10 to 0.40; Data Supplement) Taken together, these findings suggest that in patients who have previously received one or more second-generation ALK inhibitors, the presence of an ALK mutation based on tissue genotyping may identify a subgroup of patients more likely to derive durable benefit from lorlatinib. These results suggest that in patients who have failed 1 or more second-generation inhibitors, the number of ALK resistance mutations may affect the efficacy of lorlatinib, but larger studies are required to validate this finding
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